Structural modifications in the arterial wall during physiological aging and as a result of diabetes mellitus in a mouse model: Are the changes comparable?

Prévost, Gaëtan; Bulckaen, H.; Gaxatte, Cédric; Boulanger, Éric; Béraud, Guillaume; Creusy, Colette; Puisieux, François; Fontaine, P.

doi:10.1016/j.diabet.2010.08.005

Cited by 10 publications

(10 citation statements)

References 42 publications

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“…Erosion and focal dilatation of the medial layer have been described in the aortic root of ApoE −/− mice when fed an atherogenic diet with cholate or when bred on specific backgrounds (C3H or 128SvJ) [27], [28]. Our results show that diabetes (without the atherogenic diet or specific background) is a sufficient drive for medial wall erosion; in line with work showing structural modifications and disruption of the arterial media as a result of diabetes in STZ-treated C56B/J6 mice [19]. When the subvalvular plaque area was expressed as percentage of total cross sectional area, it was 16.5% larger in diabetic than in control untreated mice (p<0.05); whereas the effect of diabetes was attenuated in A-285222-treated mice (9.6% increase, n.s.).…”

Section: Resultssupporting

confidence: 90%

“…Rat anti-Moma-2 primary antibody (1 µg/mL; BMA Biomedicals, Augst, Switzerland), mouse anti-alpha-SMA (0.42 µg/mL, Sigma-Aldrich) and biotinylated secondary IgG antibodies (Vector Laboratories, Burlingame, CA) were used. Sections were counter-stained with Harris hematoxylin for determination of subvalvular lesion area, expressed both in µm 2 and as percentage of total cross sectional area to correct for potential structural differences in the arterial wall between groups [19]. Media and lumen areas were also determined based on the Harris hematoxylin staining.…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice

et al. 2013

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Objective of the StudyDiabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis.Methodology and Principal FindingsStreptozotocin (STZ)-induced diabetes in apolipoprotein E−/− mice resulted in 2.2 fold increased aortic atherosclerosis and enhanced pro-inflammatory burden, as evidenced by elevated blood monocytes, endothelial activation- and inflammatory markers in aorta, and pro-inflammatory cytokines in plasma. In vivo treatment with the NFAT blocker A-285222 for 4 weeks completely inhibited the diabetes-induced aggravation of atherosclerosis, having no effect in non-diabetic mice. STZ-treated mice exhibited hyperglycemia and higher plasma cholesterol and triglycerides, but these were unaffected by A-285222. NFAT-dependent transcriptional activity was examined in aorta, spleen, thymus, brain, heart, liver and kidney, but only augmented in the aorta of diabetic mice. A-285222 completely blocked this diabetes-driven NFAT activation, but had no impact on the other organs or on splenocyte proliferation or cytokine secretion, ruling out systemic immunosuppression as the mechanism behind reduced atherosclerosis. Instead, NFAT inhibition effectively reduced IL-6, osteopontin, monocyte chemotactic protein 1, intercellular adhesion molecule 1, CD68 and tissue factor expression in the arterial wall and lowered plasma IL-6 in diabetic mice.ConclusionsTargeting NFAT signaling may be a novel and attractive approach for the treatment of diabetic macrovascular complications.

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Section: Resultssupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice

et al. 2013

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“…Furthermore, phenylephrine-mediated contraction was also higher in ZDF than in LZ rats. These observations are in agreement with previous studies, which have shown that both aging [37], [65] and diabetes [12], [66] are associated with arterial wall hypertrophy and consequently with hypercontractility.…”

Section: Discussionsupporting

confidence: 94%

COX-2-Derived Prostanoids and Oxidative Stress Additionally Reduce Endothelium-Mediated Relaxation in Old Type 2 Diabetic Rats

et al. 2013

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Endothelial dysfunction in resistance arteries alters end organ perfusion in type 2 diabetes. Superoxides and cyclooxygenase-2 (COX-2) derivatives have been shown separately to alter endothelium-mediated relaxation in aging and diabetes but their role in the alteration of vascular tone in old diabetic subjects is not clear, especially in resistance arteries. Consequently, we investigated the role of superoxide and COX-2-derivatives on endothelium-dependent relaxation in 3 and 12 month-old Zucker diabetic fatty (ZDF) and lean (LZ) rats. Mesenteric resistance arteries were isolated and vascular tone was investigated using wire-myography. Endothelium (acetylcholine)-dependent relaxation was lower in ZDF than in LZ rats (60 versus 84% maximal relaxation in young rats and 41 versus 69% in old rats). Blocking NO production with L-NAME was less efficient in old than in young rats. L-NAME had no effect in old ZDF rats although eNOS expression level in old ZDF rats was similar to that in old LZ rats. Superoxide level and NADPH-oxidase subunits (p67phox and gp91phox) expression level were greater in ZDF than in LZ rats and were further increased by aging in ZDF rats. In young ZDF rats reducing superoxide level with tempol restored acetylcholine-dependent relaxation to the level of LZ rats. In old ZDF rats tempol improved acetylcholine-dependent relaxation without increasing it to the level of LZ rats. COX-2 (immunolabelling and Western-blot) was present in arteries of ZDF rats and absent in LZ rats. In old ZDF rats arterial COX-2 level was higher than in young ZDF rats. COX-2 blockade with NS398 restored in part acetylcholine-dependent relaxation in arteries of old ZDF rats and the combination of tempol and NS398 fully restored relaxation in control (LZ rats) level. Accordingly, superoxide production and COX-2 derivatives together reduced endothelium-dependent relaxation in old ZDF rats whereas superoxides alone attenuated relaxation in young ZDF or old LZ rats.

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“…It was previously reported that AG normalized the impaired endothelium-dependent relaxation in aorta from streptozotocin-induced diabetes mellitus mice (25) and the increased endothelin-1-induced contraction in aorta from type 2 diabetic Otsuka Long-Evans Tokushima Fatty rats (26). The mechanism of these effects was suggested to be the inhibition of AGEs formations by reacting with α,β-dicarbonyl compounds including MGO.…”

Section: Discussionmentioning

confidence: 92%

Methylglyoxal Accumulation in Arterial Walls Causes Vascular Contractile Dysfunction in Spontaneously Hypertensive Rats

et al. 2012

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Abstract. Methylglyoxal (MGO) is a metabolite of glucose and perhaps mediates diabetesrelated macrovascular complications including hypertension. In the present study, we examined if MGO accumulation affects vascular reactivity of isolated mesenteric artery from spontaneously hypertensive rats (SHR). Five-week-old SHR were treated with an MGO scavenger, aminoguanidine (AG), for 5 weeks. AG partially normalized increased blood pressure in SHR. In mesenteric artery from SHR treated with AG, increased accumulation of MGO-derived advanced glycation end-products was reversed. In mesenteric artery from SHR, AG normalized impaired acetylcholine (ACh)-induced relaxation and increased angiotensin (Ang) II-induced contraction. Reactive oxygen species (ROS) production increased in SHR mesenteric artery, and acute treatment with a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) inhibitor augmented AChinduced relaxation. Protein expression of NOX1 and Ang II type 2 receptor (AT2R) increased in SHR mesenteric artery, which was normalized by AG. Acute treatment with an AT2R blocker but not a NOX inhibitor normalized the increased Ang II-induced contraction in SHR mesenteric artery. The present results demonstrate that MGO accumulation in mesenteric artery may mediate development of hypertension in SHR at least in part via increased ROS-mediated impairment of endothelium-dependent relaxation and AT2R-mediated increased Ang II contraction.

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Structural modifications in the arterial wall during physiological aging and as a result of diabetes mellitus in a mouse model: Are the changes comparable?

Cited by 10 publications

References 42 publications

Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice

Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice

COX-2-Derived Prostanoids and Oxidative Stress Additionally Reduce Endothelium-Mediated Relaxation in Old Type 2 Diabetic Rats

Methylglyoxal Accumulation in Arterial Walls Causes Vascular Contractile Dysfunction in Spontaneously Hypertensive Rats

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